Brooker et al (1991a) [Reviewing Agency: BVL] The BVL assessed this study for both the JMPR (2004b) and EU (1998) reviews of glyphosate. There were no discrepancies between the two evaluations, although the EU report provided more data on skeletal ossification. In rats orally gavaged from GD 6 – 15 at 0, 300, 1000 or 3500 mg/kg bw/d, there were maternal deaths at 3500 mg/kg and other evidence of maternotoxicity (clinical signs and a dose-related reduction in bodyweight gain) at 1000 and 3500 mg/kg. Litter and mean foetal weights were depressed at 3500 mg/kg. The incidence of malformations was not affected by treatment but at 1000 and/or 3500 mg/kg, there were increased incidences of wavy ribs and deficits in ossification of the cranium, vertebral arches and sternebrae (see Table). The proportion of foetuses displaying skeletal anomalies was elevated significantly at 1000 and 3500 mg/kg compared with concurrent controls. The incidence of skeletal anomalies was also increased at 300 mg/kg, but lay within the HC range (the BVL also noted that the study control incidence of skeletal variations was atypically low). The finding in this particular group was therefore considered not to be treatment-related, so the NOAEL for maternotoxicity and developmental toxicity was set at 300 mg/kg bw/d. Kimmel et al (2013) set maternal and foetal NOAELs of 1000 mg/kg bw/d in an evaluation of this study, without commenting on the skeletal anomalies.

Tasker et al (1980a) [Reviewing Agencies: BVL, US EPA and Australian DoHA] According to the BVL evaluation for the EU, glyphosate was administered by gavage to rats over GD 6 – 19 at 0, 300, 1000 or 3500 mg/kg bw/d. Maternal toxicity (mortality, clinical signs and reduced bodyweight gain), enhanced foetal mortality, depressed foetal bodyweight and a higher incidence of unossified sternebrae occurred at 3500 mg/kg. At this dose there was also an increased number of foetuses with malformations (which the BVL did not describe). However, since the incidence and type of malformations were similar to those from HC data, the BVL did not ascribe them to treatment. No further information was provided. NOELs of 1000 mg/kg bw/d were therefore set for maternal and foetal toxicity.

The US EPA (1993) assessment of Tasker et al (1980a) agreed with the BVL evaluation. In the presence of maternotoxicity at 3500 mg/kg bw/d, foetal developmental effects were assessed as increased numbers of foetuses and litters with unossified sternebrae, and decreased mean foetal bodyweight. The NOAEL for maternal toxicity and developmental toxicity was set at 1000 mg/kg bw/d.

The Australian DoHA (1985) evaluated Tasker et al (1980a) in greater detail than the other two agencies but agreed with their principal findings. At 3500 mg/kg, signs of maternal toxicity comprised decreased bodyweight gain; diarrhoea, soft stools, reduced activity and rales in all dams from half way through the dosing period, and six maternal deaths. Dams receiving 300 and 1000 mg/kg showed no reaction to treatment. The NOEL for maternotoxicity was therefore set at 1000 mg/kg bw/d. Increases in the number of foetuses with unossified sternebrae (a developmental variation), dwarfism and bent tail were noted at 3500 mg/kg. However, all dwarf foetuses were in one litter, all foetuses with bent tail were from another litter, and the control and 3500 mg/kg groups had the same number of litters containing malformed foetuses. HC data indicated there were five bent tails out of 5008 foetuses, all confined to one litter out of 383. The DoHA therefore attributed dwarfism and bent tail to genetic factors and in the absence of foetal malformations at 1000 or 300 mg/kg, set a NOEL of 1000 mg/kg bw/d fetotoxicity. Assessments of this study by Williams et al (2012) and Kimmel et al (2013) made the same conclusions.

Moxon (1996a) [Reviewing Agency: BVL] This study, in which dams were orally gavaged from GD 7 – 16 at 0, 250, 500 or 1000 mg/kg bw/d, was assessed for the JMPR review only. There were no treatment-related findings, and so NOELs of 1000 mg/kg bw/d were set for maternal and developmental toxicity. The BVL’s conclusions have been corroborated independently by Kimmel et al (2013).

Suresh (1991)[Reviewing Agency: BVL] Rats received glyphosate at 0 or 1000 mg/kg bw/d by gavage between GD 6 and 15. There was no evidence of maternotoxicity, embryolethality or foetal malformations in the treated group, but there was a higher incidence of delayed ossification of the caudal vertebral arch and proximal forelimb and distal hindlimb phalanges. However, delayed ossification of other parts of the skeleton, particularly the skull, was more frequently seen in the control group. As there was “no clear and consistent impact of test compound administration” on ossification, NOELs of 1000 mg/kg bw/d were set for maternal and developmental toxicity. Kimmel et al (2013) also accepted there were no treatment-related effects in this study.

Bhide (1988a) [Reviewing Agencies: BVL and Australian DoHA] The BVL and DoHA (1992) assessments of this study were closely similar. Glyphosate was administered to rats from GD 15 to LD 21 at nominal doses of 0, 50 and 100 mg/kg bw/d. The bodyweight and food consumption of dams were unaffected, and there were no treatment-related effects on litter parameters including pup bodyweight, survival or growth. No pathological examination was performed. Both agencies set the NOEL in parents and offspring at 100 mg/kg bw/d.

Bhide (1986) [Reviewing Agencies: BVL and Australian DoHA] Again, the two agencies’ evaluations coincided. No treatment-related maternal or foetal effects were observed in rats gavaged with glyphosate at 0, 100 or 500 mg/kg bw/d on GD 6 to 15. NOELs for materno- and fetotoxicity were set at 500 mg/kg bw/d. The EU review classified this study as “supplementary” due to reporting deficiencies.

Anon (1981)[Reviewing Agency: BVL] Glyphosate was administered in the diet to rats over GD 6 – 18. Achieved doses were 0, 22, 103 and 544 mg/kg bw/d. There was no materno- or fetotoxicity, and no foetal malformations were recorded. At the highest dietary concentration, an additional group of rats was allowed to litter and nurse their pups until LD 28. Their achieved dose was 558 mg/kg bw/d. No treatment-related effects were observed either in the dams or pups. The EU classified this study as “supplementary” due to reporting deficiencies.

Stauffer Chemical Company (1982) [Reviewing Agency: Australian DoHA] Glyphosate trimesium was administered by gavage to pregnant rats over GD 6 – 20 at 0, 30, 100 or 333 mg/kg bw/d. At the high dose, there was maternotoxicity seen as mortality, clinical signs, reduced bodyweight gain and food consumption. The maternal NOEL was therefore 100 mg/kg bw/d. No treatment-related effects on foetal survival or development occurred, but mean foetal bodyweight was depressed at 333 mg/kg bw/d. A NOEL of 100 mg/kg bw/d was set for fetotoxicity (DoHA, 1991).

Studies with aminomethylphosphonic acid (AMPA)

In addition to developmental toxicity studies on the parent chemical, the EU review included BVL assessments of oral gavage studies in pregnant rats with the glyphosate metabolite AMPA. Following a range finding experiment which found no maternal or foetal effects at up to and including the highest dose of 1000 mg/kg bw/d (Holson, 1991a), AMPA was given at 0, 150, 400 or 1000 mg/kg bw/d from GD 6 through 15 (Holson, 1991b). Dams displayed hair loss and mucoid faeces at 400 and 1000 mg/kg together with transient depression in bodyweight gain and food consumption at 1000 mg/kg only. Foetal bodyweight was slightly but significantly reduced at 1000 mg/kg, but there was no evidence of developmental malformations. Accordingly, the BVL set NOELs of 150 and 400 mg/kg bw/d for maternal and foetal toxicity. Williams et al (2012) have confirmed these findings, although reporting the maternal NOEL as 400 mg/kg bw/d. No treatment-related maternal or foetal effects occurred when AMPA was administered to pregnant rats at 0, 100, 350 or 1000 mg/kg bw/d over GD 6 – 16 (Hazelden, 1992).